title: Depletion of the 26S proteasome adaptor Ecm29 increases Toll-like receptor 3 signaling.
abstract: Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA and stimulates the innate immune response. We found that depletion of extracellular mutant 29 (Ecm29), an adaptor protein that binds to a subset of 26S proteasomes (Ecm proteasomes), increased the abundance of TLR3 in human embryonic kidney-293 and HeLa cells. Loss of Ecm29 also increased the amounts of LC3β and p62, two proteins that mediate autophagy. The absence of Ecm29 enhanced TLR3 signaling, which was characterized by the increased abundance of the adaptor protein and E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 3, increased phosphorylation and activation of effector kinases downstream of TLR3, increased nuclear localization of the transcription factor interferon regulatory factor 3, and the accumulation of signaling molecules at juxtanuclear recycling endosomes. We conclude that Ecm proteasomes play a previously uncharacterized role in mediating autophagy, trafficking of TLR3, and attenuation of TLR3-dependent signaling.
authors.affiliation: 1Division of Cardiology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gorbea
authors.forename: Martin
authors.initials: M
authors.lastname: Rechsteiner
authors.forename: Jesús G
authors.initials: JG
authors.lastname: Vallejo
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C497362:ECPAS protein, human; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex